Scientists at the Centre for Translational Omics in the University College London’s Institute of Child Health have built a pipeline that takes even ultra-rare cases and consistently delivers answers with rapid turnaround. The center, known as GOSgene, may be as close as we can get to assembly-line processing of undiagnosed rare diseases, with results that give parents and children new hope for better health outcomes.

Patients with rare or novel diseases can spend years on diagnostic odysseys. Even after countless hypotheses, tests, and clinical observations, the likelihood of getting a correct diagnosis is still slim. The London team has combined next-gen sequencing, Ingenuity Variant Analysis, and dedicated funding to generate diagnoses for children with the rarest diseases. Their work is contributing to better healthcare for families around the world, and offering valuable diagnoses that can open the doors to treatment options, support groups, and more.

GOSgene functions in partnership with the Great Ormond Street Hospital, the largest pediatric research and clinical facility in Europe. Established in 2010 by UCL professor Philip Beales and funded by the hospital’s Biomedical Research Centre, GOSgene was designed to take advantage of cutting-edge DNA sequencing technologies. By pairing sequencing with the filtering power and resolution of Ingenuity Variant Analysis, the GOSgene team has helped nearly 400 families and provided answers to more than 80 distinct clinical phenotypes.

GOSgene currently uses exome sequencing to analyze samples from families. “It allows us a hypothesis-free way to look at these genomes,” says Hywel Williams, manager of GOSgene. “We use the genetics to infer the candidate genes and see how they relate to the phenotype.” Scientists at the center have begun exploring whole genome sequencing as well. “We’ve got data on about 40 whole genomes from various projects,” he says, noting that this approach may be especially useful for acute cases, where whole genome data can be used to diagnose children in intensive care. The center’s pipeline, including Ingenuity Variant Analysis, will be used for those efforts. Williams says the variant filtering application is “absolutely essential to everything that we do.”

In a recent study published in the American Journal of Human Genetics (“Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome”), Williams collaborated with scientific and clinical experts and identified a novel syndrome in three separate families. Each family had a previously undiagnosed disease thought to be unique, but the GOSgene team was able to link the conditions and characterize a new disease. Read more about this in our previous case study: Rare Disease Specialist Identify Novel Pediatric Syndrome in Three Families.

In another study, published in the European Journal of Human Genetics (“The use of whole-exome sequencing to disentangle complex phenotypes”), the GOSgene team analyzed two siblings from a consanguineous family in Bangladesh with two affected and two unaffected children. The patients had a complex phenotype that involved both peripheral neuropathy — in this case, lack of typical movement and other motor problems — as well as bronchiectasis, leading to severe chest infections. “The combination of the two phenotypes clouded the ability to give a diagnosis to this family,” Williams says. The team managed to separate this complex phenotype into two distinct components, leading to a diagnosis for one of them and better management options for the other.